dc.contributor.author | Hoe, See LE | |
dc.contributor.author | Foster, SR | |
dc.contributor.author | Wendt, L | |
dc.contributor.author | Patel, HH | |
dc.contributor.author | Headrick, JP | |
dc.contributor.author | Peart, JN | |
dc.date.accessioned | 2019-06-07T01:34:29Z | |
dc.date.available | 2019-06-07T01:34:29Z | |
dc.date.issued | 2019 | |
dc.identifier.issn | 0022-3565 | |
dc.identifier.doi | 10.1124/jpet.118.251660 | |
dc.identifier.uri | http://hdl.handle.net/10072/384322 | |
dc.description.abstract | Sustained ligand-activated preconditioning (SLP), induced with chronic opioid receptor (OR) agonism, enhances tolerance to ischemia/reperfusion injury in young and aged hearts. Underlying mechanisms remain ill-defined, although early data implicate phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) during the induction phase, and β2-adrenoceptor (β2-AR), Gs alpha subunit (Gαs), and protein kinase A (PKA) involvement in subsequent cardioprotection. Here, we tested for induction of a protective β2-AR/Gαs/PKA signaling axis with SLP to ascertain whether signaling changes were PI3K-dependent (by sustained cotreatment with wortmannin), and whether the downstream PKA target Rho kinase (ROCK) participates in subsequent cardioprotection (by acute treatment with fasudil). A protected phenotype was evident after 5 days of OR agonism (using morphine) in association with increased membrane versus reduced cytosolic levels of total and phosphorylated β2-ARs; increased membrane and cytosolic expression of 52 and 46 kDa Gαs isoforms, respectively; and increased phosphorylation of PKA and Akt. Nonetheless, functional sensitivities of β2-ARs and adenylyl cyclase were unchanged based on concentration-response analyses for formoterol, fenoterol, and 6-[3-(dimethylamino)propionyl]-forskolin. Protection with SLP was not modified by ROCK inhibition, and changes in β2-AR, Gαs, and PKA expression appeared insensitive to PI3K inhibition, although 5 days of wortmannin alone exerted unexpected effects on signaling (also increasing membrane β2-AR and PKA expression/phosphorylation and Gαs levels). In summary, sustained OR agonism upregulates cardiac membrane β2-AR expression and phosphorylation in association with increased Gαs subtype levels and PKA phosphorylation. While Akt phosphorylation was evident, PI3K activity appears nonessential to OR upregulation of the β2-AR signal axis. This opioidergic remodeling of β2-AR signaling may explain β2-AR, Gαs, and PKA dependence of SLP protection. | |
dc.description.peerreviewed | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS | |
dc.relation.ispartofpagefrom | 37 | |
dc.relation.ispartofpageto | 46 | |
dc.relation.ispartofissue | 1 | |
dc.relation.ispartofjournal | JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | |
dc.relation.ispartofvolume | 369 | |
dc.subject.fieldofresearch | Pharmacology and pharmaceutical sciences | |
dc.subject.fieldofresearchcode | 3214 | |
dc.title | Regulation of the beta-Adrenergic Receptor Signaling Pathway in Sustained Ligand-Activated Preconditioning | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dc.type.code | C - Journal Articles | |
gro.hasfulltext | No Full Text | |
gro.griffith.author | Peart, Jason N. | |
gro.griffith.author | Wendt, Lauren | |
gro.griffith.author | Headrick, John P. | |